The use of smokeless tobacco (chewing tobacco and snuff) has increased markedly in recent years in the United States, particularly among young people. The concern about this trend arises from the addictive nature of smokeless tobacco and epidemiologic evidence that long-term use greatly increases the risk of oral cancer. On the other hand, despite some animal studies, the process of smokeless tobacco carcinogenesis is poorly understand, although evidence is emerging that this may be a synergistic (or multiplicative) process involving other factors, such as viruses or local irritation, as well as the carcinogens present in smokeless tobacco. The hypothesis underlying the present proposal is that nicotine, which is present in relatively high concentrations in smokeless tobacco, and which has been shown to bring about local mucosal damage, may act synergistically with nitrosamines, which are considered putative tobacco carcinogens. This possibility will be tested in a series of studies examining the effect on hamster cheek pouch of applications of nitrosonornicotine (NNN) with and without, nicotine for periods up to 52 weeks. A known strong chemical carcinogen, dimethyl benzanthracene (DMBA), will be used as a positive control. The effects will be examined and quantified from histological sections, using standard histopathologic, criteria to determine the extent of premalignant and malignant change. By using known amounts of defined components of smokeless tobacco in a controlled model system this study avoids the difficulties encountered in many studies with whole tobacco. An understanding of smokeless tobacco carcinogenesis is clearly of the greatest importance if public health measures are to be taken to reduce the serious long-term consequences of the widespread use of the substance. Depending on the outcome of this study such measures might include reducing the content of nicotine and nitrosamines in smokeless tobacco products.